Genomes are packaged as chromatin in nucleosomes composed of core histones (H2A/H2B/H3/H4). Epigenetic processes, mediated by histone post-translational modifications, allow continued gene expression/repression in cell lineages. Understanding how such ‘marks’ establish and propagate chromatin states is critical for specifying and maintaining distinct cell types. Moreover, epigenetic states provide a source of phenotypic variation, independent of DNA sequence.
Our research focuses on how functional centromeres are specified. Centromeres are essential for chromosome segregation in all eukaryotes. Defective chromosome segregation causes aneuploidy, which can contribute to cancer progression, and in meiosis can result in trisomic individuals with reduced quality of life.
At the heart of all centromeres are specialized nucleosomes in which histone H3 is replaced by CENP-A. CENP-A exhibits extreme epigenetic character, providing the pivotal ‘mark’ for functional centromeres, making it a paradigm for chromatin-encoded mechanisms of establishment and maintenance. A complete understanding of the processes that lead to full centromere-kinetochore assembly are required in order to dissect, and ultimately intervene in, the mechanism of chromosome segregation.
This requires a complete appreciation of how two distinct types of centromeric chromatin - heterochromatin and kinetochore-associated CENP-A chromatin – are assembled.
Does centromeric DNA have intrinsic properties? Are transcription-coupled events and specific histone modifications involved? We are unravelling how genetic and epigenetic information converge to define centromere location.